Neurofibrillary tangles (NFTs) deposits are a hallmark of a variety of neuropathologies such as Alzheimer's disease (AD), progressive supranuclear palsy, frontotemporal dementia and parkinsonism linked to chromosome 17, Pick's disease, and dementia pugilistica. NFT plaques are comprised of aggregated hyperphosphorylated tau protein. Tau is a protein associated with cytoskeleton and involved in the transport of vesicles along microtubules in neurons. Under pathological conditions, tau is hyperphosphorylated and forms beta-sheet aggregates with fibrillar appearances similar to Aβ in senile plaques. Some tau-targeted therapies aim to slow disease progression by interfering with cell-to-cell transfer of soluble tau oligomers capable infecting adjacent cells by a prion mechanism. Alternatively, tau-targeted therapies aim to inhibit tau oligomerization and/or aggregation to larger fibrils and tangles (Bulic, B., et al., J. Med. Chem., 2013 56 (11), 4135-55). Such strategies warrant reliable non-invasive tau-specific biomarkers for monitoring of current tau burden and disease progression. Tau-specific PET imaging biomarkers have the potential to non-invasively monitor disease progression and also provide a direct readout of tau-targeted agent efficacy and confirmation of its mechanism of action in clinical trials (Mathis, C. A.; Klunk, W. E., Neuron 2013 79 (6), 1035-7; and Jensen, J. R., et al., J. Alzheimer's Disease: JAD 2011 26 Suppl 3, 147-57).
Several tau-selective molecules were recently discovered and radiolabeled with positron emitting radionuclides for PET imaging. One of them, [18F][A] was reported to bind tau aggregates in AD patient tissues with 22 nM affinity and demonstrated 27-fold selectivity for tau over Aβ amyloid which forms similarly structured fibrils. Initial clinical evaluation of [A] demonstrated its ability to clearly differentiate between AD patients and age matched controls. Moreover, the PET tracer distribution in patients with increasing MMSE score resembled tau localization described by the Braak score (Braak, H., et al., Acta Neuropathol 2006 112 (4), 389-404) found postmortem in tissues of patients with corresponding AD severity. Unfortunately, the oxidative metabolism of [A] led to dissociation of 18F from the molecule and accumulation of 18F fluoride in mineral bone. The undesired skull uptake can potentially interfere with quantification of cortical uptake of the tracer. See Xia, C. F., et al., Alzheimer's Dement. 2013 9 (6), 666-76; Zhang, W., et al., J. Alzheimer's Disease: JAD 2012 31 (3), 601-12; Chien, D. T., et al., J. Alzheimer's Disease: JAD 2013 34 (2), 457-68; and Chien, D. T., et al., J. Alzheimer's Disease: JAD 2014 38 (1), 171-84.
Currently there is a need for additional detectable compounds that bind to tau. In particular, there is a need for detectable compounds with improved in vivo properties, such as improved metabolism characteristics.